Comparison of pathophysiological mechanisms in idiopathic pulmonary arterial hypertension (iPAH) and schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH)

MoleculesExpressionPathways affectedVascular cells affectedTargeted therapies for iPAHSimilarities with Sch-PAHStudy designs in Sch-PAH studies[Ref]
BMPR-IICell apoptosis ↓
Inflammation ↑
EC, SMCFK506# indirectly by IL-2 inhibition+Animal study, Database study[30, 42, 43, 44–48]
Caveolin-1Cell proliferation ↑ECAnimal study[39, 43, 49]
Endothelin-1Cell apoptosis ↓
Cell proliferation ↑
EC, SMC, AFERA (bosentan, macitentan, ambrisentan)NA[43, 50]
HIF-1αCell proliferation ↑
Cell apoptosis ↓
EC, SMC, AF+Animal study[28, 43, 51]
IL-6Inflammation ↑ECTocilizumab#+/−Animal study[36, 43, 52–54]
[K+] channelsCell apoptosis ↓
Vasoconstriction ↑
SMCNA[43, 87, 55]
MIP-1αInflammation ↑MacrophageNA[43, 56]
MMP-2Cell proliferation ↑SMCNA[43, 57, 58]
MT-MMP1Cell proliferation ↑SMCNA[43]
Nitric oxideCell proliferation ↑
Clotting ↑
Inflammation ↑
EC, SMCPDE5i (sildenafil, tadalafil)
Soluble guanylate cyclase stimulators (riociguat)
+Animal study[39, 43, 50, 59]
PDGFCell proliferation ↑EC, SMC, AFPDGFR inhibitor (imatinib)+/−Case–control study[43, 60–62]
E-selectinCell proliferation ↑EC+Case–control study[62]
P-selectinCell proliferation ↑EC+Case–control study[62]
ProstacyclinCell proliferation ↑
Clotting ↑
EC, SMCProstacyclin analogues (e.g. epoprostenol, treprostinil)
Prostacyclin receptor stimulator (selexipag)
NA[43, 63–65]
CCL5/RANTESInflammation ↑MacrophageNA−−[43, 66]
TGF-βCell proliferation ↑SMC, AF+Case–control study, human necropsy study, animal study, in vitro study[31, 32, 35, 38, 40, 43, 67, 68]
TGF-βR2Cell apoptosis ↓
Inflammation ↑
EC, SMC+in vitro study[41, 43, 68, 69]
TIMP-1Cell proliferation ↑SMCNA[43, 57, 70]
VEGFCell apoptosis ↓
Cell proliferation ↑
Clotting ↑
Inflammation ↑
EC, SMC+Animal study[28, 29, 43, 71]
vWFClotting ↑
Inflammation ↑
EC, SMCNA[43, 72]
5-HT transporter/
Cell proliferation ↑
Vasoconstriction ↑
SMCNA[44, 73]

Selected pathophysiological patterns for iPAH as presented at WSPH 2018 [42], sought for similarities in Sch-PAH. BMPR-II: bone morphogenetic protein receptor type 2; HIF-1α: hypoxia-inducible factor 1-α; IL: interleukin; MIP-1α: macrophage inflammatory protein 1-α; MMP-2: matrix metalloproteinase-2; MT-MMP1: membrane-type MMP-1; PDGF: platelet-derived growth factor; TGF-β: transforming growth factor β; TGF-βR2: transforming growth factor β receptor 2; TIMP-1: tissue inhibitor of metalloproteinases-1; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor; 5-HT: serotonin; EC: endothelial cell; SMC: smooth muscle cell; AF: adventitial fibroblast; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; NA: not applicable. −: different in iPAH and Sch-PAH; +: similar in iPAH and Sch-PAH. #: drugs currently under investigation, that are not yet approved for therapy of iPAH; : negative trials in humans. Data from [43].